Cycloastragenol Ameliorates Psoriasis by Promoting Keratinocyte Autophagy via Modulating Subcellular Localization of ZKSCAN3.

Abstract

Psoriasis is a prevalent chronic skin disease. Cycloastragenol (CAG) has been shown to activate autophagy and alleviate epidermal keratinocyte hyperproliferation in psoriasis. This study aimed to clarify the mechanism of CAG-mediated autophagy in psoriasis-like models. We treated C57BL/6 mice with imiquimod cream and stimulated HaCaT cells with a cytokine mixture (C-mix) to establish mouse and cell models. Psoriasis area and severity index scores were used to evaluate pathological changes. Autophagy flux was monitored using a monomeric red fluorescent protein-green fluorescent protein-microtubule-associated protein 1 light chain 3 assay. The interaction between sirtuin 1 (SIRT1) and zinc finger containing Krüppel-associated box and SCAN domain 3 (ZKSCAN3), as well as ZKSCAN3 acetylation, was examined using co-immunoprecipitation. Our results found that CAG alleviated autophagy inhibition in the imiquimod-induced psoriasis-like mouse model and enhanced autophagy by upregulating SIRT1 expression. ZKSCAN3 inhibited autophagy in the C-mix-stimulated psoriasis-like cellular model, while SIRT1 reduced the nuclear localization of ZKSCAN3 through deacetylation. ZKSCAN3 overexpression reversed SIRT1-mediated autophagy enhancement, whereas CAG promoted autophagy by regulating the nuclear localization of ZKSCAN3. In conclusion, our findings demonstrate that CAG ameliorates autophagy inhibition by modulating the SIRT1/ZKSCAN3 axis in psoriasis.